PROJECT SUMMARY Asthma is a chronic inflammatory disease that is increasing in severity and prevalence, particularly in developed countries, and currently affects 11% of the US population. Airborne allergens, including those of the house dust mite (HDM) Dermatophagoides pteronyssinus, are the most common trigger of allergic asthma. The disease is characterized by pulmonary eosinophilic inflammation, type 2 cytokine production, goblet cell hyperplasia, and airway hyperreactivity and remodeling. Recent findings have showed that the innate immune system plays a critical role in the inflammatory response in asthma. It is believed that intrinsic properties of allergens contribute to promoting type 2 innate lymphoid cells that secrete IL-4, IL-5 and IL-13 and amplify CD4+ Th2 differentiation and inflammation. In addition, a series factors idiosyncratic to the airway and host genetics likely facilitate allergic sensitization. However, the immunological events that contribute to this outcome remain largely unclear. IL-15, a cytokine that induces expansion and maturation of natural killer (NK) cells, has been shown to be critically involved in chronic inflammatory processes in the intestinal mucosa. However, very little is known about the contribution of this cytokine to lung mucosal inflammatory responses elicited by inhalation of environmental allergens. Our preliminary findings revealed that intranasal administration of IL-15 complex reduced HDM allergen-induced pulmonary eosinophilic inflammation. Moreover, we have shown that allergic inflammatory responses elicited by allergen entering the airway was compromised in the absence of PGI2-IP receptor signaling because of the increased infiltration of NK cells into the lungs. These studies are based on our observations demonstrating a role for endogenous eicosanoids in regulating the mucosal expression of IL-15 and, de facto, the number and properties of pulmonary NK cells. We will test the overall hypothesis that: IL-15 expression in the lung is regulated by endogenous eicosanoids and this cytokine promotes the accumulation of immunoregulatory NK cells that prevent airway inflammation elicited by airborne allergens by suppressing type 2 innate lymphoid cells. To this end, the aim is to investigate the anti-inflammatory effects of IL-15 on HDM allergen- induced pulmonary inflammation and whether this effect is NK cell-dependent. Moreover, we will examine the role of eicosanoids in regulating endogenous IL-15 production and determine the mechanism of NK cell- mediated suppression of allergic airway inflammation. These studies will advance our knowledge of how IL- 15 and lung resident NK cells prevent sensitization of the airways and inflammatory responses to environmental allergens.